Although there are no effective pharmacotherapies for cocaine dependence, studies with two adrenergic blockers showed promising findings. In a human laboratory study, carvedilol, a combined alpha- and beta-adrenergic blocker, attenuated cocaine-induced heart rate and blood pressure increases and reduced cocaine self-administration behavior. Further, in an open label outpatient study, carvedilol was well-tolerated and reduced cocaine use. Consistent with these findings, clinical trials using propranolol, a beta-adrenergic blocker, showed promising results for the treatment of cocaine dependence, especially in those who report severe cocaine withdrawal symptoms. These findings, together with preclinical and clinical studies linking cocaine withdrawal with increased adrenergic activity, provide a strong scientific rationale for pursuing adrenergic blockers as potential treatments for cocaine addiction. In this study, we will test the efficacy of carvedilol, as a treatment for cocaine dependence in a randomized 14-week clinical trial. We chose carvedilol over other adrenergic blockers due to its favorable safety profile, once-daily dosing schedule, and promising preliminary finding for its efficacy in cocaine addiction. A total of 120 opioid and cocaine dependent subjects, stabilized on buprenorphine, will be randomly assigned to 25 or 50 mg/day carvedilol or placebo. To determine if the efficacy of carvedilol is moderated by withdrawal severity, the 3 treatment groups will be matched for the severity of cocaine withdrawal measured with the Cocaine Selective Severity Assessment (CSSA). The main outcome measure will be cocaine urine results, which will be obtained 3 times per week during the study. We hypothesize that carvedilol will be more effective than placebo in reducing cocaine use. We also hypothesize that the efficacy of carvedilol will be moderated by the severity of cocaine use, such that high baseline withdrawal severity will predict better treatment response. This proposal, by testing the efficacy of carvedilol and investigating the influence of withdrawal severity on carvedilol's efficacy, may result in development of more effective treatments for cocaine addiction. [unreadable] [unreadable] [unreadable]